Gout and Hyperuricemia in Japan: Perspectives for International Research on Purines and Pyrimidines in Man

One of the best-known disorders in purine metabolism is accumulation of uric acid leading to gout. Gout is a lifestyle disease, which was nicely illustrated in the joint symposium of the Japanese Society of Gout and Nucleic Acid Metabolism and of the Purine and Pyrimidine Society held in February 2011 in Tokyo, Japan. The westernization of the Japanese diet led to an increase in hyperuricemia in Japanese, which subsequently boosted research in this field, as illustrated in this symposium. As a consequence, Japanese nucleotide research also expanded, leading to the development of not only new drugs for treatment of gout, but also for other diseases such as cancer, viral infections, and cardiovascular diseases. The research on inborn errors led to the identification of various genetic polymorphisms affecting drug metabolism, revealing differences between Asians and non-Asians. Such genetic differences may also affect the enzymatic properties of an enzyme or a transporter, necessitating specific inhibitors. This knowledge will help to introduce personalization of treatment. In this symposium, the interaction between various specialties formed an excellent basis for translational research between these specialties but also from the bench to the clinic.     

Japanese guideline for the management of hyperuricemia and gout: second edition

Gout is a urate deposition disease caused by persistent hyperuricemia. Because gout patients present with a variety of clinical symptoms, it is necessary to have a guideline for the standard management and care of gout and hyperuricemia. The Japanese Society of Gout and Nucleic Acid Metabolism, a scientific society committed to study nucleic acid metabolism and related diseases, established the first edition of the "Guideline for the Management of Hyperuricemia and Gout" in 2002, and published the revised version in January 2010. This second edition is not only evidence based on a search of systemic literature, but also includes consensus levels by a Delphi exercise to determine the strength of the recommendations. A draft version of this guideline was reviewed by internal and external reviewers as well as a patient. In this guideline, key messages from each chapter are listed as statements together with the evidence level, consensus level, and strength of the recommendation. In this proceeding, several selected chapters on the clinical management of gout and hyperuricemia are described. We hope this guideline is appropriately used for the standard management and care of patients with hyperuricemia and gout in daily practice.     

Comorbidities in patients with gout

Gout is one of the most important diseases associated with hyperuricemia. Gout is characterized by acute monoarthritis with frequent flares. Some patients with gout have gouty tophi that are composed of monosodium urate crystals and inflammatory cells. In addition to tophi, gout is associated with various comorbidities such as obesity, hypertension, abnormal lipid metabolism, renal dysfunction, and urolithiasis. We examined the associations of the presence of tophi and comorbidities with demographic and disease characteristic data of gout patients. Subjects were 422 male patients with gout who visited our outpatient clinic. The patients' background data and laboratory data at the first visit were collected from patient records. We investigated the relationship between comorbidities and characteristics of patients using multiple regression models. The age of gout onset was 44 ± 13 years. The duration of gout at the first visit was 6 ± 8 years. Five percent of subjects had tophi. The presence of tophi was significantly associated with the duration of gout and maximum serum uric acid (SUA), indicating a close association of tophi with urate deposition. Reduced estimated glomerular filtration rate was associated with older age of onset, longer duration of gout, and higher levels of maximum SUA, indicating that sustained hyperuricemia relates with renal impairment of gout. Urolithiasis did not associate with gout duration and maximum SUA. The increased frequency of hypertension was associated with the duration of gout, suggesting that poor control of gout is one of the causes of hypertension. This study provides useful information for gout management and patient education.     

Novel Developments in Metabolic Disorders of Purine and Pyrimidine Metabolism and Therapeutic Applications of Their Analogs

The biennial 15^th symposium on Purine and Pyrimidine metabolism was held in Madrid, June 2013 (PP13). During the meeting, several novel developments on the diagnosis, pathophysiology, and treatment of several inborn errors of purine and pyrimidine metabolism were presented. These ranged from new drugs for gout to enzyme replacement therapies for mitochondrial diseases. A relatively novel aspect in this meeting was the interest in purine and pyrimidine metabolism in nonmammalian systems, such as parasites, mycoplasms, and bacteria. Development of novel analogs for parasite infections, cardiovascular diseases, inflammatory diseases, and cancer were also discussed.     

Epidemiology,risk factors,and lifestyle modifications for gout

Gout affects more than 1% of adults in the USA, and it is the most common form of inflammatory arthritis among men. Accumulating data support an increase in the prevalence of gout that is potentially attributable to recent shifts in diet and lifestyle, improved medical care, and increased longevity. There are both nonmodifiable and modifiable risk factors for hyperuricemia and gout. Nonmodifiable risk factors include age and sex. Gout prevalence increases in direct association with age; the increased longevity of populations in industrialized nations may contribute to a higher prevalence of gout through the disorder's association with aging-related diseases such as metabolic syndrome and hypertension, and treatments for these diseases such as thiazide diuretics for hypertension. Although gout is considered to be primarily a male disease, there is a more equal sex distribution among elderly patients. Modifiable risk factors for gout include obesity, the use of certain medications, high purine intake, and consumption of purine-rich alcoholic beverages. The increasing prevalence of gout worldwide indicates that there is an urgent need for improved efforts to identify patients with hyperuricemia early in the disease process, before the clinical manifestations of gout become apparent.     

高尿酸血症和痛风的遗传学研究进展

痛风是由高尿酸血症引发的一种常见炎性关节炎,受遗传因素和环境因素共同作用。早期研究表明,PRPS1和HPRT1等单基因稀有突变会引起嘌呤合成代谢紊乱,从而引发高尿酸血症和痛风。近年来,全基因组关联分析(Genome-wide association studies,GWAS)已检出多个导致高尿酸血症和痛风的易感位点及相关候选基因。其中SLC2A9、SLC22A11和SLC22A12基因功能缺失性突变可引起遗传性低尿酸血症,而过表达则会加强尿酸的重吸收。ABCG2、SLC17A1和SLC17A3基因功能缺陷型变异会降低肾脏和肠道对尿酸的排泄量。因此,诱发尿酸排泄障碍(高重吸收和低排泄)的基因变异是影响高尿酸血症和痛风的主要遗传因素。另外,抑制-激活生长因子系统、转录因子、细胞骨架以及基因和环境的互作等因素也一定程度影响血液尿酸水平。在中国汉族人群中,两个新发现的易感基因RFX3和KCNQ1可能造成免疫应答受损和胰岛B细胞功能缺陷,从而直接或间接引起高尿酸酸血症和痛风。本文系统综述了高尿酸血症和痛风的遗传学研究,以促进人们对高尿酸血症和痛风发病机理的理解。     

Innate immunity functional gene polymorphisms and gout susceptibility

Gout is a common autoinflammatory disease characterized with elevated serum urate and recurrent attacks of intra-articular crystal deposition of monosodium urate. Accumulating evidence has demonstrated that MSU crystal-induced inflammation is a paradigm of innate immunity and the TLRs, NALP3 inflammasome and IL1R pathways are involved in gout development. Innate immunity components containing TLR2, TLR4, CD14, NALP3, ASC, Caspase-1 and CARD-8 are essential in the development of gouty inflammation. Recent studies suggest that innate immunity component gene functional mutations contribute to the development of autoinflammatory diseases including hereditary periodic fever syndrome, arthritis as well as inflammatory bowel disease. Taking into account these genetic findings, we would like to propose a novel hypothesis that the gene functional mutations might make innate immunity components as attractive susceptibility candidates and genetic markers for gout. Further clinical genetic studies need to be performed to confirm the role of innate immunity in the etiology of gout.     

Genomewide scan for gout in taiwanese aborigines reveals linkage to chromosome 4q25

Gout is a disorder of uric-acid metabolism. The Pacific Austronesian population, including Taiwanese aborigines, has a remarkably high prevalence of hyperuricemia and gout, which suggests a founder effect across the Pacific region. We report here a genomewide linkage study of 21 multiplex pedigrees with gout from an aboriginal tribe in Taiwan. From observations of familial clustering, early onset of gout, and clinically severe manifestations, we hypothesized that a major gene plays a role in this trait. Using 382 random polymorphic markers spread across 22 autosomes, we demonstrated a highly significant linkage for gout at marker D4S2623 on chromosome 4q25 (P=.0002 by nonparametric linkage [the NPL(all) statistic]; empirical P=.0006; LOD=4.3, P=4.4x10-6 by logistic regression). When alcohol consumption was included as a covariate in the model, the LOD score increased to 5.66 (P=1.3x10-6). Quantitative traits, including serum uric acid and creatinine, also showed a moderate linkage to this region. To our knowledge, this is the first genome-scan report to identify a genetic locus harboring a gout-susceptibility gene.     

痛风与单纯性高尿酸血症人群高脂血症的对比分析

目的:对比分析痛风与单纯高尿酸血症合并高脂血症的情况。方法:收集青岛大学附属医院痛风专病门诊2009年5月至2016年1月收治的痛风患者7207例(男性6759例,女性448例),单纯高尿酸血症患者2095例(男性1852例,女性243例)。测量受试者身高、体重、腰围、臀围、血压、空腹血糖(FPG)、血甘油三酯(TG)、血胆固醇(TC)及血尿酸(UA),计算并比较两组高甘油三脂血症、高胆固醇血症的患病率,并分析其在痛风发生中的独立作用。结果:痛风组高甘油三酯血症和高胆固醇血症的患病率分别为57.8%、47.5%;单纯高尿酸血症组为51.8%、52.9%;两组率相比的比值比,高甘油三脂血症1.274[95%CI(1.155,1.404)],胆固醇血症0.805[95%CI(0.730,0.887)]。按性别分层分析,男性痛风组高甘油三脂血症、高胆固醇血症患病率分别为56.2%,46.8%;单纯高尿酸血症组分别为52.3%,52.6%。两组率相比的比值比,高甘油三脂血症1.25[95CI%(1.13,1.39)],高胆固醇血症0.80[95CI%(0.72,0.89)]。女性中痛风组高甘油三脂血症、高胆固醇血症患病率分别为52.2%,58.90%;单纯高尿酸血症组分别为46.6%,58.0%;两组差异无统计学意义。高甘油三脂血症与痛风的发生正相关OR=1.29,95%CI(1.12,1.48),高胆固醇血症与痛风的发生负相关OR=0.80,95%CI(0.73,0.89)。结论:痛风与单纯高尿酸血症患者存在不同的脂代谢状态,高甘油三酯血症可能是单纯高尿酸血症发展为痛风的危险因素。     

痛风及高尿酸血症动物模型的研究现状和评价

痛风是一种以血尿酸增高为特征的代谢性疾病 ,近年来随着我国人民生活水平的提高 ,高尿酸血症和痛风的发病率逐年上升 ,因而研制防治痛风和高尿酸血症的药物已成为当前医药界研究的热点 ,但实验动物模型的困难严重地影响着研究工作的开展。本文对目前常见的痛风和高尿酸血症实验动物模型进行了较系统的简介 ,并根据笔者的研究经验进行了简要评价 ,供致力于该方面研究的学者参考。     

Epidemiology of gout

Gout is the most prevalent form of inflammatory arthropathy. Several studies suggest that its prevalence and incidence have risen in recent decades. Numerous risk factors for the development of gout have been established, including hyperuricaemia, genetic factors, dietary factors, alcohol consumption, metabolic syndrome, hypertension, obesity, diuretic use and chronic renal disease. Osteoarthritis predisposes to local crystal deposition. Gout appears to be an independent risk factor for all-cause mortality and cardiovascular mortality and morbidity, additional to the risk conferred by its association with traditional cardiovascular risk factors.     

The Inhibitory Activity of Natural Products to Xanthine Oxidase

The natural products have a new chemical structure and biological active diversity, so they are favored by scientific researchers. Gout is a high incidence and high-risk disease, and the current treatments are not satisfactory. Xanthine oxidase (XO) is a key enzyme responsible for the development and progression of various metabolic and oxidative stress-related diseases. Excessive activity of XO leads to elevated serum urate levels, which in turn leads to the development of hyperuricemia. This review mainly introduces the recent progress of the new research on the anti-gout activity of natural products that could provide new treatment methods for gout and information for the discovery and development of new anti-gout drugs.     

Gout. Epidemiology of gout

Gout is the most prevalent form of inflammatory arthropathy. Several studies suggest that its prevalence and incidence have risen in recent decades. Numerous risk factors for the development of gout have been established, including hyperuricaemia, genetic factors, dietary factors, alcohol consumption, metabolic syndrome, hypertension, obesity, diuretic use and chronic renal disease. Osteoarthritis predisposes to local crystal deposition. Gout appears to be an independent risk factor for all-cause mortality and cardiovascular mortality and morbidity, additional to the risk conferred by its association with traditional cardiovascular risk factors.     

Contemporary topics in immunology: approaches to immunotherapy emerging from basic research.

The seventh symposium in the series "Contemporary Topics in Immunology" was held on April 21, 1991, at the FASEB meeting in Atlanta, Georgia. It was sponsored by the National Institute of Allergy and Infectious Diseases, The American Association of Immunologists, and the Clinical Immunology Society. Five topics were discussed by leading researchers in areas of immunology that currently are of exceptional interest and show promise of leading to new advances in the prevention and treatment of human diseases. The topics included: the interactions between immunogenic peptides, class I MHC molecules and T cell receptors; initiation, maintenance, and breakdown of self-tolerance in B lymphocytes; inflammatory disease in HLA-B27 transgenic rats; properties and functions of interleukin-10; and transforming growth factor-beta in reproductive immunology. The exceptional quality of the presentations in this seventh symposium exemplified perfectly the path of basic research that often leads from the laboratory to the clinic.     

Ecological annotation of genes and genomes through ecological genomics

Ecological genomics is a research field that aims to determine how a genome or a population of genomes interacts with its environment across ecological and evolutionary timescales. This matter was the central theme of the symposium on Ecological Genomics that took place at the First meeting of the Canadian Society for Ecology and Evolution, held at the University of Toronto in May 2007. Through their research on a diverse array of organisms, the various speakers illustrated how ecology and evolution benefit from genomics, and indirectly how genomics can benefit from evolutionary ecology.     

痛风及微生态防治的相关进展

痛风病主要是由于人体中尿酸结晶沉积在某些部位所引起的急性或慢性病变。痛风病的治疗由来已久,针对其病因和发病机制陆续出现了一些治疗方法,随着微生态学的不断研究,发现乳酸菌具有降解人体内嘌呤的作用,进而能够降低尿酸结晶的含量,为痛风病的治疗开辟了一个新的领域。     

高尿酸血症和痛风的流行病学及其危险因素的研究进展

高尿酸血症和痛风是由于长期嘌呤代谢紊乱所引起的一种代谢性疾病,随着各国经济的发展,其患病率在全球范围呈逐年升高的趋势,因此相关研究也日益增多.本文就近年来有关高尿酸血症与痛风的流行病学及其危险因素的研究作一综述,并着重阐述高尿酸血症与糖尿病关系的相关研究进展.     

Toll-like receptors in rheumatic diseases: Are we paying a high price for our defense against bugs?

In the last decade Toll-like receptor (TLR) research has led to new insights in the pathogenesis of many rheumatic diseases. In autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis TLR signaling is likely to be involved in tolerance breakthrough and chronic inflammation via combined Fc gamma receptors and TLR recognition of immune complexes. Furthermore, inflammatory diseases like psoriatic arthritis and gout also show more and more evidence for TLR involvement. In this review we will discuss the involvement of TLR signaling in several rheumatic diseases and stress their similarities and differences based on recent findings.     

Advances in purine and pyrimidine metabolism in health and diseases

ABSTRACT

In June, 2015, the Purine and Pyrimidine Society organized the 16th biennial symposium on Purine and Pyrimidine metabolism at the Faculty House of Columbia University, New York City. This exciting meeting focused on these important molecules, new developments in inborn errors of metabolism; therapeutic analogs. In addition, the biochemistry of mammalian and non-mammalian systems were discussed. Due to significant advances in molecular medicine, the boundaries between clinical and basic sciences have merged into exciting translational research, of which a small portion was highlighted in the presymposium.